Biology subjects

Kaiser, A. M.

Publications and source records attributed to Kaiser, A. M..

3 recordsLinked to original sources

bioRxiv2026

AP-1 specifies developmental versus fibrotic extracellular matrix transcriptional programs in the lung

Lung function requires an elastic extracellular matrix (ECM). However, the adult lung does not regenerate the elastic architecture established during development, and deposition of fibrous ECM characterizes many lung diseases. We generated a multimodal, single-nuclei atlas across development, homeostasis, aging, and fibrosis to identify lung fibroblast populations, transcriptional programs, and regulatory logic governing these divergent matrix outcomes. We discovered differential AP-1 transcription factor activity orchestrates distinct ECM programs via preferential binding to TPA-responsive elements (TRE) in fibrosis and cAMP-responsive elements (CRE) in development. Antagonizing AP-1 TRE-signaling in lung fibroblasts repressed the fibrotic program and re-engaged a developmental, elastogenic state, and MEK inhibition produced similar transcriptional phenotypes. Pathological fibroblasts in interstitial lung diseases upregulated TRE motif activity, and expression of downstream fibrosis signatures positively correlated with disease severity. These results uncover AP-1 as a critical signaling hub governing lung fibroblast ECM deposition that can potentially be exploited to improve disease outcomes.

cell biology↗

bioRxiv2024

Substrate stiffness dictates unique paths towards proliferative arrest in WI-38 cells

Finite replicative potential is a defining feature of non-transformed somatic cells, first established by Leonard Hayflick in vitro using WI-38 human lung fibroblasts. Once proliferative capacity is exhausted due to telomere shortening, cells enter into a state called replicative senescence, which can be avoided through ectopic expression of telomerase reverse transcriptase (hTERT). As WI-38 cells approach replicative arrest, molecular pathways linked to mechanotransduction are induced, including YAP signaling, but the potential interplay between replicative lifespan and the mechanical environment of the cell remains unexplored. Here, we investigate the influence of mechanosensation on the trajectory towards replicative arrest taken by WI-38 cells by growing cells on substrates of varying stiffnesses. Matrix softening slowed proliferation, altered cellular phenotypes, and shortened proliferative lifespan while hTERT expression abrogated or reduced these responses. Our analyses of bulk and single-cell RNA-sequencing and ATAC-sequencing revealed the emergence of a unique G1 transcriptional state on soft substrates, characterized by an AP-1 transcription factor program, which failed to manifest with hTERT expression. Together, these findings reveal how the mechanical environment alters WI-38 cell proliferative lifespan and dictates unique paths towards growth arrest.

cell biology↗

bioRxiv2021

The Mettl3 epitranscriptomic writer amplifies p53 stress responses

The p53 transcription factor, encoded by the most frequently mutated gene in human cancer, plays a critical role in tissue homeostasis in response to stress signals. The mechanisms through which p53 promotes downstream tumor suppressive gene expression programs remain, however, only superficially understood. Here, we used tandem affinity purification and mass spectrometry to reveal new components of the p53 response. This approach uncovered Mettl3, a component of the m6A RNA methyltransferase complex (MTC), as a p53-interacting protein. Analysis of Mettl3- deficient cells revealed that Mettl3 promotes p53 protein stabilization and target gene expression in response to DNA damage. Mettl3 acts in part by competing with the p53 negative regulator, Mdm2, for binding to the p53 transactivation domains to promote methyltransferase-independent stabilization of p53. In addition, Mettl3 relies on its catalytic activity to augment p53 responses, with p53 recruiting Mettl3 to p53 target genes to co-transcriptionally direct m6A modification of p53 pathway transcripts to enhance their expression. Mettl3 also promotes p53 activity downstream of oncogenic signals in vivo, in both allograft and autochthonous lung adenocarcinoma models, suggesting cooperative action of p53 and Mettl3 in tumor suppression. Accordingly, we found in diverse human cancers that mutations in MTC components perturb expression of p53 target genes and that MTC mutations are mutually exclusive with TP53 mutations, suggesting that the MTC enhances the p53 transcriptional program in human cancer. Together, these studies reveal a fundamental role for Mettl3 in amplifying p53 signaling through protein stabilization and epitranscriptome regulation.

cancer biology↗